tbuckley/cabot-search huggingface dataset:
Platelets amino acids spectrum and coagulation in patients with atherosclerosis
Authors: I Melnychuk, VN Kramarova, VG Lizogub
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): O.O.Bogomolets National Medical University Relevance: Amino acids are one of the important group of myocardial metabolites. Today metabolomic analysis has become an essential tool for understanding the pathophysiology of cardiovascular disorders [1, 3]. Coagulation factors interact with platelets by binding to platelet receptors directly or indirectly or by cleaving of the platelet receptors. Arterial thrombosis as a most life threating atherosclerosis (AS) complication is characterized by significant interplay between platelets and coagulation [2]. Therefore, it is important to find pathogenic links between changes in platelet structure and coagulation data. Materials and methods 78 patients were investigated. All patients were divided into two groups – 20 patients without AS (control group) and 58 patients with AS (mean group). Diagnosis was verified by carotid and peripheral arteries ultrasound. Statistically all groups were compatible by the main clinical features (age, gender, concominant disorders, etc.). For amino acid platelet determination, platelet-rich plasma was obtained after blood centrifugation at 3000 g 15 min of 10 ml of the remaining plasma. One milliliter of platelet-rich plasma was centrifuged at 2,500 g for 15 min to obtain a platelet pellet that was frozen at –20°C until assayed. All the samples were stored for a maximum of 3 mounth. Platelets amino acid spectrum was checked by ion exchange liquid column gas chromatography. Results Patients of the mean group has significantly differences compared with control group: decreasing of taurine (6.54±9.49 vs 5.94±4.36 mkmol/107), threonine (0.48±1.69 vs 0.22±1.24 mkmol/107), glycine (2.10±3.79 vs 1.02±2.11 mkmol/107) and glutamine (2.54±5.70 vs 1.88±2.76 mkmol/107) levels; increasing alanine (1.99±4.03 vs 2.81±3.06 mkmol/107), valine (0.96±1.98 vs 1.63±1.26 mkmol/107) and isoleucine (0.53±1.84 vs 2.91±1.61 mkmol/107) levels. Also in mean group acquired leucine (2.51±0.93 mkmol/107) that was not present in control group. Total amount of branch-chained amino acids (BCAA) in platelets is also increased significantly. Therefore, in mean group patients were significant higher-level activated partial thromboplastin time (APTT) (34.3±2.87 vs 28.8±3.29 s) and lower fibrinogen (205±17 vs 213±2 mg/dl). Direct significant correlation was checked between glycine (r=0,634; p&amp;lt;0,05), alanine (r=0,587; p&amp;lt;0,05) and fibrinogen, also between APTT and platelets BCAA (r=0,724; p&amp;lt;0,01). Conclusion We obtained reliable changes in platelets amino acid spectrum and coagulation tests in patients with atherosclerosis. In addition, significant correlations between themes can be related with pathogenic platelets changes. In any case more deeper studies are desirable.
MEDB-81. Combined inhibition of CDK11 and EZH2 results in regression of MYC-amplified medulloblastoma
Authors: Dong Wang, Bethany Veo, Angela Pierce, Sujatha Venkataraman, Rajeev Vibhakar
Journal: Neuro-Oncology (2022)

Abstract We explored an shRNA library screen on 20 cyclin-dependent kinases to establish cyclin-dependent kinase 11 (CDK11) as a critical mediator in MYC-driven medulloblastoma. The effect and molecular mechanism of CDK11 in the proliferation and growth of medulloblastoma were investigated in vitro. Pharmaceutic inhibitors and genetic depletion of CDK11 resulted in cessation of tumor growth in xenograft mouse models. Through combination chemical screening, we identified that 5-FU enhanced the apoptosis which induced by inhibition of CDK11 in medulloblastoma cells. In addition, we found CDK11 is a significant candidate kinase participating in the negative control of Wnt/b-catenin signaling. Down-regulation of CDK11 led to the accumulation of Wnt/β-catenin signaling receptor complexes through activation of transmembrane Frizzled (FZD) receptors which is suppressed by H3K27Me3. RNASeq and cut&amp;run revealed that Cdk11 and mediator associated Cdk8 kinase regulate a common set of genes. Lack of Cdk8 and Cdk11 impaired Ezh2 recruitment and the establishment of histone H3 lysine 27 tri-methylation. We concluded that combined EZH2 and CDK8/CDK11 inhibitors treatment concurrently activated Wnt signaling may be an effective treatment for Group 3 medulloblastoma.
AGA White Paper: Challenges and Gaps in Innovation for the Performance of Colonoscopy for Screening and Surveillance of Colorectal Cancer
Authors: Srinadh Komanduri, Jason A. Dominitz, Linda Rabeneck, Charles Kahi, Uri Ladabaum, Thomas F. Imperiale, Michael F. Byrne, Jeffrey K. Lee, David Lieberman, Andrew Y. Wang, Shahnaz Sultan, Aasma Shaukat, Heiko Pohl, V. Raman Muthusamy
Journal: Clinical Gastroenterology and Hepatology (2022)
Racial differences in treatment patterns and outcomes of first-line (1L) therapies for advanced renal cell carcinoma (aRCC) in the real-world (RW) setting.
Authors: Daniel M. Geynisman, Jonathan K. Kish, Angelica Falkenstein, Stephen Huo, Viviana Del Tejo, Lisa Rosenblatt, Sarah Guttenplan, Alexandrina Balanean, Bruce A. Feinberg
Journal: Journal of Clinical Oncology (2022)

4548 Background: In 1L therapy for aRCC, nivolumab plus ipilimumab (NIVO+IPI) and pembrolizumab plus axitinib (PEM+AXI) have demonstrated significantly improved clinical outcomes versus sunitinib in phase III trials. African American/Black (AA) patients are grossly underrepresented in all aRCC trials. Little is known about the impact of racial differences on the use of 1L therapies and clinical outcomes in the RW setting. Methods: This retrospective chart review included AA and White American (WA) patients diagnosed with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC)/Memorial Sloan Kettering Cancer Center (MSKCC) intermediate/poor (I/P)-risk aRCC who initiated on 1L NIVO+IPI, PEM+AXI, or tyrosine kinase inhibitor (TKI) monotherapy with sunitinib, pazopanib, or cabozantinib. Patients’ demographic/clinical characteristics and outcomes were abstracted from medical charts by treating oncologists. Use of 1L therapy, treatment discontinuation, and clinical outcomes including disease response, landmark progression-free survival (PFS), landmark overall survival (OS), and treatment-related adverse event (TRAE) rates were assessed descriptively by race. Results: Of 473 patients, 95 (20.1%) were AA, and 378 (79.9%) were WA patients. Median follow-up was 10.9 months. A higher proportion of AA vs. WA patients had received 1L TKI monotherapy (21.1% vs. 16.1%). Treatment discontinuation rate was higher in AA vs. WA patients (49.5% vs. 43.4%). Treatment response was lower in AA than WA patients (overall response rate [ORR]: 58.8% vs. 74.8%; complete response [CR]: 8.2% vs. 11.4%). The TRAE rate was slightly lower in AA vs. WA patients (25.3% vs. 32.5%). Stratified clinical outcomes including landmark PFS and OS rates at 6 and 9 months are shown in the Table. Conclusions: In this RW I/P-risk aRCC cohort, fewer AA patients were treated with standard of care immune-oncology (IO)-based therapy vs. WA patients, which may contribute to differences in therapy discontinuation and survival outcomes. Also, even with short follow-up, clinically meaningful ORR differences are noted in AA and WA patients. [Table: see text]
Trends of utilization and comparison between AMS® vs. Coloplast Titan® Inflatable Penile Prostheses (IPPs) in Italy – results from a national registry (INSIST-ED)
Authors: N. Schifano, G. Antonini, C. Bettocchi, F. Colombo, G. Liguori, S. Fiordelise, A. Vitarelli, M. Silvani, M. Paradiso, C. Ceruti, F. Varvello, F. Palumbo, A. Avolio, D. Pozza, G. Franco, M. Bitelli, E. Conti, E. Caraceni, E. Pescatori, A. Salonia, A. Palmieri, F. Deho', P. Capogrosso
Journal: European Urology (2022)
SPECT-defined, active bone marrow–sparing, volumetric-modulated arc therapy reduces the incidence of acute hematologic toxicity in patients with locally advanced cervical cancer who receive chemoradiotherapy.
Authors: Shan Bing Wang, JiaPei Liu, Yuming Jia, Kaijian Lei
Journal: Journal of Clinical Oncology (2022)

5527 Background: Acute haematologic toxicity is the most common side effect of chemoradiotherapy in patients with locally advanced cervical cancer.We are aim to test the efficacy of defined active bone marrow sparing volumetric-modulated arc therapy reduces grade 3 or higher (grade 3+) acute haematologic toxicity for patients with locally advanced cervical cancer treated with chemoradiotherapy. Methods: This was a prospective, single-center, open label, randomized clinical trial that enrolled locally advanced cervical cancer.Patients were randomized to 99m Tc sulfur colloid SPECT-defined active bone marrow sparing volumetric-modulated arc therapy group (ABMS group) or control group.The control group received weekly cisplatin concurrently with volumetric-modulated arc therapy(VMAT),followed by high-dose-rate intracavitary brachytherapy. The active bone marrow sparing volumetric-modulated arc therapy group additionally received 99m Tc sulfur colloid SPECT-defined active bone marrow dose constrain. The primary endpoint was the incidence of grade 3 or higher (grade 3+) acute haematologic toxicity. Secondary objectives included acute gastrointestinal toxicity, planning Target Volume (PTV) coverage and dosimetric parameters of organs at risk(OARs). Results: A total of 148 patients with Federation of Gynaecology and Obstetrics(FIGO) stage IB-IIIB fromJanuary 2017 to April 2019 were randomized，and 146 were treated(74 in ABMS group and 74 in control group). The median follow-up was 20.0 months.The incidence of grade 3 or higher (grade 3+) acute haematologic toxicity in the ABMS group was 29.7%,significantly lower than the 48.6% incidence in the control group(p = 0.03).The incidence of grade 3+ neutropenia (ABMS group：20.3%,control group:36.5%;p = 0.04), Grade 3+ leukopenia (ABMS group：25.7%,control group:44.6%;p = 0.02) and Grade 3+ lymphopenia (ABMS group：4.1%,control group:14.9%;p = 0.04) were significantly differences between the two group.The were no differences in Grade 3+ anemia (ABMS group：1.4%,control group:5.5%;p = 0.37) and Grade 3+ acute gastrointestinal toxicity(ABMS group：1.4%,control group:1.4%;p = 1.00) between the two group.The number of patients completing five cycles of cisplatin in the ABMS group was 88.5%,,significantly higher than the 75% in the control group(p = 0.02).There were no differences in PTV coverage and dosimetric parameters of OARs between the two group. Conclusions: SPECT-defined active bone marrow sparing VMAT signifificantly reduced grade 3+ acute haematologic toxicity,and improved chemotherapy delivery compared with control group. Clinical trial information: ChiCTR-IOR-16010214.
ctDNA in treatment response monitoring in patients with relapsed gynecologic malignancies.
Authors: Jason Russell Williams, Kassondra Grzankowski, Kayla Castaneda, Jose Salvador Saldivar, Concepcion Diaz-Arrastia, Georges Azzi, Hemant Sindhu, Young Kwang Chae, Ekaterina Kalashnikova, Brittany Nicosia, Shilpa Tekula, Giby V. George, Meenakshi Malhotra, Adam ElNaggar, Alexey Aleshin
Journal: Journal of Clinical Oncology (2022)

e17501 Background: The role of immunotherapy in gynecologic malignancies continues to evolve. Use of immune checkpoint blockade (ICB) agents have consistently demonstrated less than a 15% response rate in ovarian, cervical, and subsets of endometrial cancer. Given the limited number of responders, a novel approach to treatment monitoring is needed to better sequence therapies. Circulating tumor DNA (ctDNA) surveillance in patients treated with ICB is one such approach that has been shown to predict clinical benefit. We sought to evaluate this approach in patients with recurrent gynecologic malignancies managed with ICB therapy. Methods: In this retrospective analysis of real-world data, plasma samples (n = 208) from 28 patients with recurrent/metastatic ovarian (n = 8), endometrial (n = 14), and cervical (n = 6) cancers were identified as having received ICB therapy. A personalized and tumor-informed multiplex PCR assay (Signatera™ bespoke mPCR NGS assay) was used for the detection of ctDNA in plasma samples. Serial time points were collected to monitor ctDNA levels in response to immunotherapy. Results: Response assessment results and longitudinal plasma samples were available for 19 patients. Pre-ICB plasma samples were available for 11 patients. Of these ctDNA was detected in 73% (8/11) of patients. All patients with progressive disease (10/10) had rising ctDNA levels that preceded radiological findings by a median of 2.8 months. One patient with rising ctDNA concentration presented with stable disease by imaging at the last follow-up. The remaining 8 patients demonstrated response to therapy that coincided with a declining or negative ctDNA level; 5 with partial response had a decline in ctDNA level prior to imaging (n = 3) or lack of ctDNA detection (n = 2), and 3 with complete response remained ctDNA negative, prior to imaging. Patients that exhibited a rise in ctDNA concentration (n = 11) (consecutive time points) while undergoing ICB therapy were associated with resistance to treatment (HR = 4.58 95%CI: 1.048-20.03, p = 0.04). TMB and MSI status (binary) were not predictive of response in univariate (p = 0.8, p = 0.9) analyses. Conclusions: ctDNA monitoring during the course of immunotherapy for relapsed gynecologic malignancies allows for accurate determination of therapeutic response and early prediction of disease progression. This enables timely assessment with imaging, and change in treatment plan. Our data suggest that patients with gynecologic malignancies may benefit from personalized, tumor-informed ctDNA testing to guide treatment decisions. Prospective studies are needed to establish the clinical utility of ctDNA monitoring in patients with gynecologic malignancies undergoing systemic therapies.
Phase II study of alisertib as a single agent for treating recurrent or progressive atypical teratoid/rhabdoid tumor
Authors: Santhosh A Upadhyaya, Olivia Campagne, Catherine A Billups, Brent A Orr, Arzu Onar-Thomas, Ruth G Tatevossian, Roya Mostafavi, Jason R Myers, Anna Vinitsky, Daniel C Moreira, Holly B Lindsay, Lindsay Kilburn, Patricia Baxter, Amy Smith, John R Crawford, Sonia Partap, Anne E Bendel, Dolly G Aguilera, Kim E Nichols, Evadnie Rampersaud, David W Ellison, Paul Klimo, Zoltan Patay, Giles W Robinson, Alberto Broniscer, Clinton F Stewart, Cynthia Wetmore, Amar Gajjar
Journal: Neuro-Oncology (2022)

Abstract Background Recurrent atypical teratoid/rhabdoid tumor (AT/RT) is, most often, a fatal pediatric malignancy with limited curative options. Methods We conducted a phase II study of Aurora kinase A inhibitor alisertib in patients aged &amp;lt;22 years with recurrent AT/RT. Patients received alisertib once daily (80 mg/m2 as enteric-coated tablets or 60 mg/m2 as liquid formulation) on Days 1–7 of a 21-day cycle until progressive disease (PD) occurred. Alisertib plasma concentrations were measured in cycle 1 on Days 1 (single dose) and 7 (steady state) and analyzed with noncompartmental pharmacokinetics. Trial efficacy end point was ≥10 participants with stable disease (SD) or better at 12 weeks. Results SD (n = 8) and partial response (PR) (n = 1) were observed among 30 evaluable patients. Progression-free survival (PFS) was 30.0% ± 7.9% at 6 months and 13.3% ± 5.6% at 1 year. One-year overall survival (OS) was 36.7% ± 8.4%. Two patients continued treatment for &amp;gt;12 months. PFS did not differ by AT/RT molecular groups. Neutropenia was the most common adverse effect (n = 23/30, 77%). The 22 patients who received liquid formulation had a higher mean maximum concentration (Cmax) of 10.1 ± 3.0 µM and faster time to Cmax (Tmax = 1.2 ± 0.7 h) than those who received tablets (Cmax = 5.7 ± 2.4 µM, Tmax = 3.4 ± 1.4 h). Conclusions Although the study did not meet predetermined efficacy end point, single-agent alisertib was well tolerated by children with recurrent AT/RT, and SD or PR was observed in approximately a third of the patients.
The physiological underpinnings of life-saving respiratory support
Authors: Irene Telias, Laurent J. Brochard, Simone Gattarello, Hannah Wunsch, Detajin Junhasavasdikul, Karen J. Bosma, Luigi Camporota, Daniel Brodie, John J. Marini, Arthur S. Slutsky, Luciano Gattinoni
Journal: Intensive Care Medicine (2022)
Sleep and allostatic load: A systematic review and meta-analysis
Authors: Dinne S. Christensen, Robert Zachariae, Ali Amidi, Lisa M. Wu
Journal: Sleep Medicine Reviews (2022)

The detrimental effects of sleep disturbances on health and wellbeing are well-established but not fully understood. The allostatic load model has been suggested as a framework for understanding the adverse effects of sleep disturbances. We conducted a systematic review and meta-analysis to examine the associations of sleep disturbance and sleep duration with allostatic load. PubMed, PsycINFO, Embase, and Web of Science were searched for records relating to sleep and allostatic load published from 1993 to January 14th, 2022. Two independent raters screened 395 titles and abstracts and 51 full texts. Data were extracted from 18 studies that were assessed for methodological quality. Of these, 17 studies of 26,924 participants were included in the meta-analysis. Sleep disturbance was significantly associated with higher allostatic load (effect size correlation [ESr] = 0.09, p < 0.001), and the association was weaker in samples with a larger proportion of women. When compared to normal sleep, long sleep was significantly associated with higher allostatic load (ESr = 0.12, p = 0.003). Results indicated heterogeneity. No association was found for short sleep (ESr = 0.05, p = 0.069) or sleep duration (ESr = -0.06, p = 0.36). Future research should identify mechanisms and directionality in longitudinal studies.
MOONSTONE/GOG-3032: Interim analysis of a phase 2 study of niraparib + dostarlimab in patients (pts) with platinum-resistant ovarian cancer (PROC).
Authors: Leslie M. Randall, David M. O'Malley, Bradley J. Monk, Robert L. Coleman, Stephanie Gaillard, Sarah F. Adams, Linda R. Duska, Fabio Cappuccini, Heather Dalton, Robert W. Holloway, Marilyn Huang, Hye Sook Chon, Noelle Gillette Cloven, Adam ElNaggar, Roisin Eilish O'Cearbhaill, Steven E. Waggoner, Zebin Wang, Eric Zhi, Vivek Samnotra, Panagiotis A. Konstantinopoulos
Journal: Journal of Clinical Oncology (2022)

5573 Background: PROC is poorly responsive to anticancer therapy. PARP inhibitors such as niraparib may increase neoantigen load and synergize with anti-PD-1 agents. TOPACIO reported a preliminary objective response rate (ORR: 18%) and disease control rate (DCR: 65%) to niraparib + pembrolizumab in pts with OC of any BRCA status. MOONSTONE sought to determine efficacy in pts without BRCA mutation ( BRCAm). Methods: In this phase 2 open-label, single-arm study, eligible pts received 1–3 prior lines of therapy including platinum, taxane, and bevacizumab, had RECIST v1.1 radiographic progression within 6 mo of last platinum line and had no known germline BRCAm. Pts were treated with niraparib 300/200 mg PO daily (based on weight/platelets) and 500 mg dostarlimab IV Q3W (cycles 1–4) followed by 1000 mg Q6W until disease progression, toxicity or consent withdrawal. Programmed death-ligand 1 (PD-L1) positive status was determined by Ventana SP263 assay using visually-estimated combined positive score ≥5%. The primary endpoint was investigator-assessed ORR per RECIST v1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), DCR, and safety. Futility was prespecified as ≤5 responses in the first 40 pts. Results: At interim analysis (data cutoff Oct 6, 2021), 41 pts were enrolled; median age was 65.0 y (range 35–77). At baseline, 8 (20%)/22 (54%)/11 (27%) pts had received 1/2/3 prior lines of therapy, respectively; 26 (63%) pts had primary resistance to platinum therapy and 15 (37%) were sensitive to first platinum treatment. Overall, tumors were PD-L1+/PD-L1–/unknown in 13 (32%)/25 (61%)/3 (7%), respectively. Efficacy results are shown in the Table. Treatment-related adverse events were reported in 95% of pts, most commonly nausea (56%), fatigue (34%), vomiting (32%), and anemia (29%). Conclusions: PROC remains difficult to treat; the ORR observed with niraparib + dostarlimab did not reach the threshold for 2nd-stage accrual in this cohort of pts with PROC, no known BRCAm, and prior bevacizumab treatment. PD-L1 status did not predict response; HRD testing is in process. Although DCR was 29%, futility was declared based on low ORR. The safety of the combination was similar to the safety profile of each monotherapy. Clinical trial information: NCT03955471. [Table: see text]
Real-world evaluation of AG plus PD-1 antibody in old patients with advanced unresectable pancreatic cancer.
Authors: Bin Wang, Zenglei He, Liang Xue, Shengmin Mei, Li Xu, Qi Ling
Journal: Journal of Clinical Oncology (2022)

e16226 Background: Unresectable pancreatic cancer (PC) is associated with fatal outcomes despite chemotherapy and radiation. PD-1 antibodies might provide favorable long-term survival in combination with chemotherapy according to previous clinical trials and pilot studies. In this study, we conducted a real-world evaluation of PD-1 antibody in old patients with unresectable PC. We also aimed to explore biomarkers for the early prediction of PD-1 antibodies response. Methods: This is a single-arm, single-center, real-world study. Primary Objectives: ORR. Secondary Objectives: DCR, OS, PFS, Safety(CTCAE). Exploratory Objectives: The alteration of molecular biomarkers to PD-1 antibodies treatment including IL-2, IL-4, IL-10, IL-16, TNF¦Á and IFN-¦Ã, ect. Key eligibility criteria: Histopathologically confirmed advanced unresectable PC; Without systematic treatment; ¡Ý60 years old; ECOG PS 0 or 1; Evaluated by mRECIST PD-1 plus AG, Q3W Surgery Until disease progression, unacceptable toxicity, or up to 2 years. Results: From Jan 2021 to Dec 2021, 10 unresectable PC patients were enrolled in Yuhang campus, the first affiliated hospital, Zhejiang university school of medicine, which their baseline characteristics were listed in Table. A total of 9 patients were finally included and analyzed. Clinical decisions were made by multi-disciplinary team. The treatment efficacy was evaluated by mRECIST. A total of 9 patients were assessable for response. ORR was 33.3%, with 3/9 partial response (PR). 5/9 patients were stable disease (SD), and DCR was 88.9%. Conversion therapy uses rational immunotherapy and chemotherapy and so on combined with MDT assessment to translate initial unresectable case to resectable one, which obviously prolongs survival time and improves quality of life. For patients with surgically unresectable PC 2 patients were successfully transformed. The rate of overall surgical conversions was 22.2%. The most common adverse events were anemia (6 [60%] patients). There were no treatment-related level 4 and 5 adverse events. There was no treatment-related cardiotoxicity. No patients were interrupted due to adverse events. Conclusions: PD-1 antibody plus Chemotherapy demonstrates significant clinical activity and favorable tolerability in old patients with advanced unresectable PC, and DCR was 88.9%.[Table: see text]